Process for the manufacture of 4-(2-butenylidene)-3,5,5-trimethyl-2-cyclohexen-1-one

ABSTRACT

A method for the manufacture of the four geometric isomers of 4-(2-butenyl)idene)-3,5,5-trimethy-2-cyclohexen-1-one is provided. The process comprises pyrolyzing a compound of the formula ##STR1## wherein R represents lower-alkyl-oxycarbonyl, aryl-oxycarbonyl, or, preferably, lower-alkanoyl, benzoyl or substituted benzoyl.

This application is a division of application Ser. No. 07/399,208 filed:Aug. 28, 1989, U.S. Pat. No. 5,015,779 PROCESS FOR THE MANUFACTURE OF4-(2-BUTENYLIDENE)-3,5,5-TRIMETHYL-2-CYCLOHEXEN-1-ONE.

SUMMARY OF THE INVENTION

The process of this invention provides a novel method for themanufacture of 4-(2-butenylidene)-3,5,5-trimethyl-2-cyclohexen-1-one (I)(megastigmatrienone), a known flavoring component of tobacco. Moreparticularly, the invention provides a process for the manufacture of amixture of the four possible geometric isomers of megastigmatrienone, asshown below. wherein 1a represents the ZZ-isomer; 1b represents theZE-isomer; 1c represents EZ-isomer; and 1d represents the EE-isomer.##STR2##

The novel method comprises pyrolyzing a compound of the formula ##STR3##wherein R represents a lower-alkanoyl group, for example an alkanoylgroup containing from one to six carbon atoms; an optionally substitutedbenzoyl group, for example, one substituted by a lower alkyl groupcontaining from one to six carbon atoms such as a methyl group; a loweralkyl-oxycarbonyl group of the formula ##STR4## or an aryl-oxycarbonylgroup of the formula ##STR5## R^(I) is preferably an alkyl group of oneto six carbon atoms such as methyl or ethyl. R^(II) is preferably phenylor tolyl. Examples of R are acetyl, propionyl, butyroyl, caproyl,benzoyl and toluoyl. Acetyl is a preferred substituent.

The compounds of formula II may exist as a mixture of two possiblegeometric (Z- and E-) isomers, namely ##STR6## For purposes of thepresent invention, it is preferred to use a mixture of the two isomers.

The compounds of formula II are conveniently prepared by esterifying4-(2-hydroxybutylidene)-3,5,5-trimethyl-2-cyclohexen-1-one (III),preferably as the Z- and E-isomer mixture ##STR7##

The compound of formula III may be prepared by reacting(2,6,6-trimethyl-4-oxo-2-cyclohexen-1-ylidene)acetaldehyde (IV),preferably as the Z- and E-isomer mixture ##STR8## with anorganometallic reagent.

The compounds of formulas II and III are novel and are also an object ofthis invention.

A number of synthetic methods for the manufacture of megastigmatrienoneare available from the prior art:

(1) U.S. Pat. No. 3,211,157

(2) U.S. Pat. No. 3,217,718

(3) E. Demole, P. Enggist, Helv. Chim. Acta 57, 2087-2089, (1974)

(4) B. M. Trost, J. L. Stanton, JACS 97, 4018-4025, (1975)

(5) S. Torrii, J. Inokuchi, H. Ogawa, Bull. Chem. Soc. Japan 52,1233-1234, (1979)

(6) O. Takazawa, H. Tamura, K. Kogami, K. Hayashi, Bull. Chem. Soc.Japan 55, 1907, (1982)

(7) German Offenlegungsschrift 35 16 931.

These syntheses all suffer from disadvantages such as:

a) the use of problematic reagents (2), (7);

b) non-uniform reaction products (3);

c) expensive reagents (4), (5), (6); and

d) difficultly accessible starting materials (1).

None of these disadvantages are associated with the present process.

The present process has the further advantage that the isomerdistribution of Ia to Id comes close to the isomer distribution which isfound in nature. (See e.g. T. Fujimori, R. Kasuga, H. Kaneko, M.Noguchi, Central Research Institute, The Japan Tobacco and Salt PublicCorporation, Yokohama, Japan; Presentation at the 7th InternationalCongress of Essential Oils, Kyoto, Japan, 1977, FIG. 4 "Gaschromatogramm of the neutral volatile fraction of leaves before curingand aging"; see also Tobacco Report, October 1983, 42.)

ILLUSTRATION OF THE PREFERRED EMBODIMENTS

The pyrolysis of compound II is conveniently carried out at temperaturesof about 400°-600° C., especially at about 450°-550° C., under an inertgas atmosphere, such as nitrogen or in a noble gas atmosphere. Themixture of isomers of compound I obtained from the pyrolysis may beconveniently purified by standard methods such as distillation.

Compound II may be prepared by the esterification of4-(2-hydroxybutylidene)-3,5,5-trimethyl-2-cyclohexen-1-one (III). Thisesterification may be conveniently carried out using customary acylatingagents, such as acyl halides, especially the chloride, or acidanhydrides. The use of acid anhydrides is preferred. The acylation isconveniently carried out in the presence of a base, e.g. an organicamine such as pyridine or dimethylamine. An inert solvent, e.g. ahydrocarbon or an ether, such as hexane, cyclohexane, toluene, diethylether, etc. may be used but is not necessary. A suitable temperaturerange is that of about 20° C.-80° C. (See Organikum, Org. Chem.Grundpraktikum VEB Deutscher Verlag der Wissenschaften, Berlin (1986),page 402 et seq.)

The preparation of the hydroxy compound III may be carried out byreacting the ketoaldehyde IV with an appropriate organometallic reagentsuch that the side-chain at the aldehyde function is lengthened by twocarbon atoms. A convenient reagent is accessible by the reaction of C₂H₅ MgX with a reagent of the formula MX₂, or C₂ H₅ MgX with (C₂ H₅)₂ M,or is (C₂ H₅)₂ M, wherein M represents zinc or cadmium and X is bromine,chlorine or iodine. The use of C₂ H₅ MgX/MX₂ is preferred, particularlyC₂ H₅ MgCl/ZnCl₂.

The reaction may be carried out in a manner analogous to those known inthe art. (See for example Organic Reactions VIII, 31; J. Wiley, NewYork-London (1954) 31.) The halide, C₂ H₅ MgX, in ether, may be added atroom temperature, to the halide MX₂, followed by addition of an etherealsolution of IV. The working-up is carried out by extracting III with anorganic solvent.

The ketoaldehyde IV is known. (See for example H. Mayer, M. Montavon, R.Ruegg, O. Isler, Helv. Chim. Acta 50, Fasc. 6 (1967), page 1606, or U.S.Pat. No. 2,827,481.) An especially suitable isomer mixture of IV for thepresent synthesis consists of about 25 to 35% of the E-isomer and toabout 75 to 65% of the Z-isomer. Such a mixture is readily accessible,for example, from 3,5,5-trimethyl-4-hydroxy-4-ethynylcyclohex-2-en-1-oneby rearrangement using catalysts based on silylvanadates in a mannerknown per se. Tris(triphenylsilyl)-vanadate is preferred. (See L.Cerveny and Vlastimil Ruzicka, Parfumerie und Kosmetik, 69 (1), 9,(1988).)

The isomer distribution of IV is essentially retained in the subsequentsteps described above.

ILLUSTRATION OF THE PREFERRED EMBODIMENTS Example

a) Lithium (15 g, 2.2 mol) in small pieces is added within one hour to900 ml of ammonia at -35° C. Acetylene is conducted through the mixtureuntil the blue color has disappeared and a grey suspension results.Ketoisophorone (150 g, 1 mol) is then added dropwise. The ammonia isevaporated within 12 hours. An orange colored residue remains.Subsequently, 1 liter of ice/water is added, the mixture is treatedwhile stirring with ether and then with 2N HCl and thereafter made acidwith conc. HCl. The phases are separated and the aqueous phase isextracted four times with ether. The ether extracts are washed twicewith water and with saturated sodium chloride solution, dried, filteredand concentrated. In this manner there are obtained 166 g of crude3,5,5-trimethyl-4-hydroxy-4-ethynylcyclohex-2-en-1-one. This crudeproduct is dissolved almost completely in 500 ml of ether and thencooled to -25°. In this manner there are obtained 86.2 g (48%) ofcrystalline 3,5,5-trimethyl-4-hydroxy-4-ethynylcyclohex-2-en-1-one. Themother liquor is dissolved in 140 ml of isopropyl ether and cooled to0°. In this manner there are obtained a further 25 g (14%) of crystalsof the desired compound.

b) Triphenylsilanol (22 g) and 80 g (0.45 mol) of3,5,5-trimethyl-4-hydroxy-4-ethynylcyclohex-2-en-1-one and 1.6 g ofstearic acid are dissolved in 800 ml of xylene, treated with 1.92 ml ofvanadium isopropylate and heated to reflux temperature while stirring.After 31/2 hours the reaction mixture is cooled and washed with 5%sodium bicarbonate, whereby an emulsion results. The organic phase isthen separated, the emulsion is also separated and extracted with ether.The organic phases are dried over magnesium sulphate and concentrated.The residue (117.9 g) is distilled (oil bath 130°-170°; 0.001 mm Hg). Inthis manner there are obtained 51.8 g (64.8%) of(2,6,6-trimethyl-4-oxo-2-cyclohexen-1-ylidene)acetaldehyde (Z:E=about3:1).

c) Ethyl iodide (122.6 g, 0.786 mol) in 100 ml of ether is addeddropwise within 40 minutes to 19.1 g (0.786 mol) of magnesium in ether.The mixture is left to react at room temperature for 12 hours whilestirring. The reagent formed is added dropwise within 40 minutes to107.14 g (0.786 mol) of zinc chloride in 400 ml of ether (slightexothermic reaction). The mixture is left to react at reflux temperaturefor 11/2 hours while stirring. Then, 100 g (0.562 mol) of(2,6,6-trimethyl-4-oxo-2-cyclohexen-1-ylidene)acetaldehyde dissolved in400 ml of ether are added at room temperature within 30 minutes whilestirring. After half of the addition a viscous paste forms, but thisagain dissolves. The mixture is subsequently stirred at reflux for 4hours and at room temperature for 48 hours. The reaction mixture ispoured on to ice and extracted with ether. The organic solution iswashed neutral three times with 300 ml of water each time and then with300 ml of saturated sodium chloride solution. The organic phase is driedover magnesium sulphate and evaporated. There are obtained 104 g of amixture of(Z)-4-(2-hydroxybutylidene)-3,5,5-trimethyl-2-cyclohexen-1-one and(E)-4-(2-hydroxybutylidene)-3,5,5-trimethyl-2-cyclohexen-1-one which isreacted immediately.

d) Acetic anhydride (54.9 g, 0.54 mol) is added at room temperature to104 g (0.5 mol) of the above mixture in 500 ml of pyridine. Afterstirring at room temperature for 18 hours the pyridine is distilled off.The residue is dissolved in ether and washed twice with 2N HCl, withsaturated sodium bicarbonate solution, with water and with saturatedsodium chloride solution and dried over magnesium sulphate. Crudeproduct (107.15 g) is distilled. (B.p. @ 0.001 Torr, 117°-140°, heatingbath 136°-185°). In this manner there are obtained 86 g of4-(2-acetoxybutylidene)-3,5,5-trimethyl-2-cyclohexen-1-one [Z/E=73/26]corresponding to 61.4% of theory based on(2,6,6-trimethyl-4-oxo-2-cyclohexen-1-ylidene)acetaldehyde.

e) The pyrolysis apparatus used in this example consists of:

a) Pre-heating tube: Pyrex, 30 cm, 2.5 cm φ, Raschig rings 7×7 mm,heating mantle.

b) Main heating tube: Quartz, 32 cm, 2.5 cm φ, Raschig rings 6×6 cm,muffle furnace.

4-(2-Acetoxybutylidene)-3,5,5-trimethyl-2-cyclohexen-1-one (90 g, 0.36mol) is pyrolyzed (pre-heating tube 190°, main heating tube 500°) within6 hours under a nitrogen stream of 6 ml/minute and under a water-jetvacuum (11 mm Hg) with a dropwise addition rate of 3-5 drops per minute.The reaction product is collected in a flask which is cooled to -70° C.Two head fractions are subsequently distilled over a 10 cm Widmer columnand have the following characteristics:

Fraction 1: Bath 128°; 0.001 Torr; b.p. 40°-98°; 4.9 g.

Fraction 2: Bath 128°; 0.001 Torr; b.p. 98°; 5.1 g.

The residue is subjected to short-path distillation at 120°/0.1 Torr. Inthis manner there are obtained 55.1 g (80%) of4-(2-butenylidene)-3,5,5-trimethyl-2-cyclohexen-1-one. Isomer ratio:19,48% ZZ, 41,30% ZE, 12,34% EZ, 26,86% EE.

We claim:
 1. A compound of the formula ##STR9## wherein R representshydrogen, lower-alkanoyl, benzoyl, substituted benzoyl,lower-alkyl-oxycarbonyl or aryl-oxycarbonyl.
 2. A compound according toclaim 1 wherein R represents hydrogen, lower alkanoyl, benzoyl orsubstituted benzoyl.
 3. A compound according to claims 1 or 2 which is amixture of the E- and the Z-geometric isomers.
 4. A compound accordingto claim 3 wherein the ratio of the E- to the Z-isomer is about25-35:65-75.
 5. A compound according to claim 4 wherein the loweralkanoyl contains an alkyl group having from one to six carbon atoms andthe substituted benzoyl is substituted with an alkyl group having fromone to six carbon atoms.
 6. A compound according to claim 5 wherein Rrepresents hydrogen, acetyl, propionyl, butyroyl, caproyl, benzoyl ortoluoyl.